1. Technical Field
The present invention relates to the field of xcex23-Adrenoreceptor agonists and to methods of their preparation, formulation and use to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals. More particularly, the present invention relates to the field of treating obesity and overweight conditions in animals, particularly humans and other mammals and associated effects of conditions associated with obesity and overweight, including Type II diabetes mellitus (non-insulin dependent diabetes), insulin resistance, glucose intolerance, hypothyroidism, morbid obesity, and the like.
2. Prior Art
It was long thought that obesity was a consequence of self-indulgence and undisciplined behavior. Obesity was seen as evidence of gluttony, through a lack of will or capacity for self-discipline The overweight have been disparaged, and thinness has been celebrated. Indeed, the perception of thinness as a major aspect of human beauty and attractiveness has become endemic in modern culture, and overweight conditions and obesity has increasingly grown to be an unacceptable condition for social reasons.
Masked by these cultural icons are the hard medical facts: for many individuals, a tendency to overweight and even obesity are often symptoms of organic disease or disorders of the metabolism, associated with serious and even life-threatening conditions. In medical economic terms alone, the costs attributable to overweight and obesity are staggeringly high.
A wide variety of approaches to the alleviation of obesity have ebbed and flowed though modern culture, ranging from a diverse collection of dietary strategies, to drugs, to surgical interventions, to hypnosis. All have met with indifferent success at best. Some have proved to be outright quackery. Others have proved to be effective only for the short-term, with loss of effectiveness over time. Still others have proved to be generally or at least partially successful so long as the regimen is sustained, but long term compliance is difficult to attain and in some cases has proved hazardous to other aspects of health and well-being. Some surgical procedures have had some successes, but as with any invasive procedures, there are risks. Some approaches to weight loss and control, in the extreme, lead to conditions which are themselves pathological, such as bulimia and anorexia nervosa. Other effects are less extreme, but still highly undesirable, such as amennorhea, vitamin and essential nutrient deficiencies, and the like.
A great deal of the difficulty in the art and practice of obesity and overweight management has been a consequence of attention focused on the control of appetite, and reducing the amount of food intake. It has long been the belief of many that only by the control of caloric intake is it possible to regulate body weight and fat deposition and utilization. Since appetite is controlled and regulated in the brain, brain pharmacology and the alteration of brain chemistry has been a primary focus of weight regulation and control efforts. Such approaches have led to addictions to appetite suppressants, to primary pulmonary myopathy, cardiac valve damage, and to reports of serotonin disruptions and disorders and psychotic episodes among users. Morbities and mortalities have been unacceptably high.
In another aspect of technology relating to fat is the dietary emphasis on limiting dietary fat intake. For those who eat meats, there is increasing emphasis on low fat content meats in the carcasses of the animals employed in food stocks. Much recent efforts have been devoted to the production of beef, pork, poultry and the like with reduced fat content. Breeding patterns are being manipulated and generic engineering of farm animals is being directed at lowering fat content of the animals. The techniques of fattening of animals intended for table meat production is highly developed, but is gradually being limited by the emphasis on limiting dietary fats and interest in leaner carcass animals.
Only in very recent times has obesity been addressed in relation to the metabolic pathways of the body and their role and import in fat storage and usage in the body.
Recent research has elucidated some of the mechanisms of obesity and overweight, and has revealed that much of the limitation of prior and current weight-loss techniques stems from the fact that they are biochemically and particularly metabolically unsound and incapable of stimulating, regulating and modulating metabolism of fats in adipose tissues. Without these characteristics, it is now known, weight loss and control strategies are likely to fail or to produce conditions as bad as or worse than the weight problems they are intended to alleviate. Without heroic dedication and discipline, and even fanaticism, by the subject, most strategies are short term in their weight loss and control effects.
Increasing efforts have been directed to biochemical research into the mechanisms of fat deposition and metabolism and into stimulating, regulating and modulating metabolism of fats in adipose tissues. Considerable recent progress has been made.
Among the biochemical work of note has been the recent recognition of a role of xcex2-Adrenoreceptor activity in the metabolism of fats. It has been recognized that agonists for xcex2-Adrenoreceptors have, in some cases, produced marked weight loss in animals, particularly humans and other mammals.
More recently, the loss of weight has been identified with the xcex2-Adrenoreceptor sub-type, xcex23-Adrenoreceptors. The specific structure of the xcex23-Adrenoreceptor has not been characterized, but it has been demonstrated to be a distinct cellular structure, distinguishable from the xcex21-Adrenoreceptor and the xcex22-Adrenoreceptor sites previously identified.
It has been demonstrated that compounds which are significant xcex23-Adrenoreceptor agonists produce marked weight loss in animals, particularly humans and other mammals, and that the loss is sustained with continuation of the administration of such compounds. These compounds provide potent regulation of fat metabolism. The compounds employed to date are also agonists for the xcex21-Adrenoreceptor and the xcex22-Adrenoreceptor sites. The lack of selectivity represents unwanted side effects of such compounds, and the compounds known as xcex23-Adrenoreceptor agonists to date are not suitable candidates for therapeutic usage because of the unwanted and dangerous side effects.
3. Problems and Needs in the Art
The existing strategies for weight and body fat regulation are inadequate. The current strategies are ineffective, unsafe, or both. Whether through diet manipulations or through drug usage, or combinations of such strategies, there is a lack of a clear path to safe and effective regulation of body weight and body fat which is safe and effective, which can provide significant and long lasting relief from the health consequences of overweight and obesity and the conditions associated therewith, and from the disease conditions which are aggravated by overweight and obesity.
It is clear that the art lacks and needs therapeutic agents which are highly potent and highly selective xcex23-Adrenoreceptor agonists for effective stimulation, regulation and modulation of metabolism of fats in adipose tissues.
It is also clear that the art lacks and needs agents which are effective xcex23-Adrenoreceptor agonists free of unwanted side effects, and which are safe for stimulating, regulating and modulating metabolism of fats in adipose tissues.
It is clear that the art lacks and needs agents which are effective at regulating the body fat of animals, particularly humans and other mammals, both in the reduction of body weight in the obese and the attendant health problems and issues, and in the production of low fat table meats from domesticated animals for human consumption.
It is an object of the present invention to provide novel compounds which are safe and effective xcex23-Adrenoreceptor agonists.
It is another object of the present invention to provide syntheses of such xcex23-Adrenoreceptor agonists.
Another object of the present invention is the provision of safe and effective xcex23 Adrenoreceptor formulations for administration to stimulate, regulate and modulate metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
Still another object of the present invention is to provide safe and effective administration of xcex23-Adrenoreceptor agonists for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
Yet another object of the present invention is to provide a safe and effective regimen for causing and promoting weight loss in humans, and for the maintenance of healthy and personally desired body fat levels.
Still another object of the present invention is to provide safe and effective adjuncts to the husbandry of domesticated animals for the production of low fat dietary meats for human consumption.
The primary objective of the present invention is to provide for weight and body fat regulation through modalities which are effective and safe. The present invention provides a clear path to safe and effective regulation of body weight and body fat which is safe and effective, which can provide significant and long lasting relief from the health consequences of overweight and obesity and the conditions associated therewith, and from the disease conditions which are aggravated by overweight and obesity.
These and related objectives are met by the terms of the present invention as set out in detail in the following specification and defined in the claims appended hereto.
Compounds which are highly potent and highly specific xcex23-Adrenoreceptor agonists are provided. The compounds are formulated into pharmaceutical preparations and administered for stimulating, regulating and modulating metabolism of fats in adipose tissues in animals, particularly humans and other mammals.
The compounds of the invention have the structure: 
R1 and R2 are each independently members selected from the group consisting of H, OH, Cl, NO2, CH3SO2NH, NH2, CH3O and weak acids of the structure R7xe2x80x94NH, where R7 is an acyl group, wherein at least one of R1 and R2 is OH. It is generally preferred that R2 be OH.
R3, R4 and R5 are variously and independently members selected from I, Br, Cl, F, OCH3, CH3, alkyl, alkylaryl, aminoalkyl, thioalkyl, and O-alkyl. Preferably, R4 and R5 are each a halogen, the same or different.
R6 is an acid moiety which forms an acid salt with the NH group. R6 is desirably HCl or (COOH)2.
While the racemic mixtures are active, selective, and bioavailable, we have found that the isolated isomers are ordinarily of more particular interest. The S(xe2x88x92) isomers are preferred, as they will be found to have the highest selectivity and the highest bioavailability. The R(+) isomers are also of interest, as the R-isomers are in some cases easier to isolate.
The compounds are formulated into pharmaceutical carriers to serve as highly selective, effective and safe xcex23-Adrenoreceptor agonists to provide long term weight control.
In humans, the compositions are administered to control body fat levels, and to maintain acceptable body fat levels over time.
In domesticated animals, the compositions are administered to attain desirably low fat content in carcass meats intended for human consumption.